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EP2970256B1 - New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors - Google Patents

New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors Download PDF

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Publication number
EP2970256B1
EP2970256B1 EP14708891.8A EP14708891A EP2970256B1 EP 2970256 B1 EP2970256 B1 EP 2970256B1 EP 14708891 A EP14708891 A EP 14708891A EP 2970256 B1 EP2970256 B1 EP 2970256B1
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EP
European Patent Office
Prior art keywords
substituted
pyrrole
pyrrolo
alkyl
hexahydro
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German (de)
French (fr)
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EP2970256A1 (en
Inventor
Jérôme HERT
Daniel Hunziker
Patrizio Mattei
Harald Mauser
Guozhi Tang
Lisha Wang
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to EP14708891.8A priority Critical patent/EP2970256B1/en
Priority to RS20191633A priority patent/RS59682B1/en
Priority to PL14708891T priority patent/PL2970256T3/en
Priority to HRP20192274TT priority patent/HRP20192274T1/en
Priority to SI201431438T priority patent/SI2970256T1/en
Publication of EP2970256A1 publication Critical patent/EP2970256A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LPA) production and thus modulators of LPA levels and associated signaling, for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • ATX autotaxin
  • LPA lysophosphatidic acid
  • the present invention provides novel compounds of formula (I) wherein
  • ATX Autotaxin
  • LPC lysophosphatidyl choline
  • LPA bioactive signaling molecule lysophosphatidic acid
  • LPA can elicit a wide range of cellular responses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis and others.
  • LPA mediates its effects via signaling to several G protein coupled receptors (GPCRs); the first members were originally denoted Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-1(vzg-1) but are now called LPA receptors.
  • GPCRs G protein coupled receptors
  • Edg endothelial cell differentiation gene
  • ventricular zone gene-1(vzg-1) ventricular zone gene-1(vzg-1) but are now called LPA receptors.
  • the prototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7.
  • the ATX-LPA signaling axis is involved in a large range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression and altered responses to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.
  • the compounds of formula (I) or their pharmaceutically acceptable salts can be used for the treatment or prophylaxis of diseases, disorders or conditions that are associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).
  • LPA lysophosphatidic acid
  • the compounds of formula (I) or their pharmaceutically acceptable salts herein inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling.
  • Autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
  • the ATX-LPA axis has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular conditions, metabolic conditions such as obesity and/or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as acute and chronic organ transplant rejection.
  • Objects of the present invention are the compounds of formula (I) and their aforementioned salts and their use as therapeutically active substances, a process for the manufacture of the said compounds, pharmaceutical compositions, medicaments containing the said compounds or their pharmaceutically acceptable salts, the said compounds or their pharmaceutically acceptable salts for use in the treatment or prophylaxis of disorders or conditions that are associated with the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA), particularly in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and-chronic organ transplant rejection, and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer
  • alkenyl denotes a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenyl group is ethenyl.
  • alkoxy denotes a group of the formula -O-R', wherein R' is an alkyl group.
  • alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Particular alkoxy group include isopropoxy.
  • alkoxyalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group.
  • alkoxyalkoxy group examples include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy.
  • Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.
  • alkoxyalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group.
  • alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.
  • alkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group.
  • alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl and isopropoxymethyl.
  • Particular alkoxyalkyl group include include methoxymethyl, methoxyethyl and isopropoxymethyl.
  • alkoxycarbonyl denotes a group of the formula -C(O)-R', wherein R' is an alkoxy group.
  • alkoxycarbonyl groups include groups of the formula -C(O)-R', wherein R' is methoxy or ethoxy.
  • Particular alkoxycarbonyl group include groups of the formula -C(O)-R', wherein R' is methoxy.
  • alkoxyhaloalkyl denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an alkoxy group.
  • alkoxyalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl and ethoxytrifluoropropyl.
  • alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl group is methyl.
  • alkylcarbonyl denotes a group of the formula -C(O)-R', wherein R' is an alkyl group.
  • alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is methyl or ethyl.
  • Particular alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is methyl.
  • alkylcarbonylamino denotes a group of the formula -NH-C(O)-R', wherein R' is an alkyl group.
  • alkylcarbonylamino groups include groups of the formula -NH-C(O)-R', wherein R' is methyl or ethyl.
  • Particular a alkylcarbonylamino groups include groups of the formula -NH-C(O)-R', wherein R' is methyl.
  • alkylsulfanyl denotes a group of the formula -S-R', wherein R' is an alkyl group.
  • alkylsulfanyl groups include groups of the formula -S-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Particular alkylsulfanyl groups include group of the formula -S-R', wherein R' is methyl.
  • alkylsulfinyl denotes a group of the formula -S(O)-R', wherein R' is an alkyl group.
  • alkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Particular alkylsulfinyl groups include group of the formula -S(O)-R', wherein R' is methyl.
  • alkylsulfonyl denotes a group of the formula -S(O) 2 -R', wherein R' is an alkyl group.
  • alkylsulfonyl groups include groups of the formula -S(O) 2 -R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Particular alkylsulfonyl groups include group of the formula -S(O) 2 -R', wherein R' is methyl.
  • alkylsulfonylamino denotes a group of the formula -NH-S(O) 2 -R', wherein R' is an alkyl group.
  • alkylsulfonylamino groups include groups of the formula -NH-S(O) 2 -R', wherein R' is methyl or ethyl.
  • Particular a alkylsulfonylamino groups include groups of the formula -NH-S(O) 2 -R', wherein R' is methyl.
  • amino denotes a -NH 2 group.
  • aminoalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aminogroup.
  • aminoalkyl include aminomethyl, aminoethyl, amino-1-methyl-ethyl, aminopropyl, aminomethylpropyl and aminopropyl. Particular examples are aminomethyl and haminoethyl.
  • aminosulfonyl denotes a -S(O) 2 -NH 2 group.
  • carbonyl denotes a -C(O)- group.
  • cyano denotes a -C ⁇ N group.
  • cycloalkoxy denotes a group of the formula -O-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
  • Particular cycloalkoxy group is cyclopropoxy.
  • cycloalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group.
  • cycloalkoxyalkyl groups include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
  • cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms.
  • cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common.
  • monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.
  • Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.
  • cycloalkylalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group.
  • examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.
  • cycloalkylalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group.
  • cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.
  • cycloalkylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group.
  • examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and adamantanylethyl.
  • cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and adamantanylethyl.
  • cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl, adamentanylmethyl and adamantanylethyl.
  • cycloalkylcarbonyl of the formula -C(O)-R', wherein R' is a cycloalkyl group.
  • cycloalkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is cyclopropyl.
  • cycloalkylsulfanyl denotes a group of the formula -S-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is cyclopropyl.
  • cycloalkylsulfinyl denotes a group of the formula -S(O)-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is cyclopropyl.
  • cycloalkylsulfonyl denotes a group of the formula -S(O) 2 -R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfonyl groups include groups of the formula -S(O) 2 -R', wherein R' is cyclopropyl.
  • haloalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms.
  • perhaloalkoxy denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.
  • haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.
  • Particular haloalkoxy group is trifluoromethoxy.
  • haloalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms.
  • perhaloalkyl denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group is trifluoromethyl.
  • haloalkylsulfanyl denotes a group of the formula -S-R', wherein R' is a haloalkyl group.
  • haloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is trifluoromethyl.
  • haloalkylsulfinyl denotes a group of the formula -S(O)-R', wherein R' is a haloalkyl group.
  • haloalkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is trifluoromethyl.
  • haloalkylsulfonyl denotes a group of the formula -S(O) 2 -R', wherein R' is a haloalkyl group.
  • haloalkylsulfonyl groups include groups of the formula -S(O) 2 -R', wherein R' is trifluoromethyl.
  • halogen and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro and fluoro.
  • hydroxy denotes a -OH group.
  • hydroxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
  • examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.
  • hydroxyhaloalkyl denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an hydroxy group.
  • exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl.
  • Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.
  • naphthylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a naphthynaphthyl. Particular naphthylalkenyl group is naphytylethenyl.
  • naphthylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a naphthyl.
  • Particular naphthylalkyl groups are naphthylmethyl, naphthylethyl and naphthylpropyl.
  • naphthyloxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a naphthyloxy group.
  • exemplary naphthyloxyalkyl groups include naphthyloxymethyl, naphthyloxyethyl and naphthyloxypropyl.
  • phenoxy denotes a group of the formula -O-R', wherein R' is a phenyl.
  • phenoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a phenoxy group.
  • exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyl and phenoxypropyl.
  • Particular alkoxyalkyl group is phenoxymethyl.
  • phenylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a phenyl.
  • Particular phenylalkenyl group is phenylethenyl.
  • phenylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a phenyl.
  • Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl. Further particular phenylalkyl group is benzyl.
  • phenylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a phenyl. Particular phenylalkynyl group is phenylethynyl.
  • phenylcyloalkyl denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced a phenyl.
  • Particular phenylcycloalkyl group is phenylcyclopropyl.
  • pyridinylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a pyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.
  • pyridinylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a pyridinyl.
  • Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl and pyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.
  • pyridinylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a pyridinyl.
  • Particular pyridinylalkynyl group is pyridinylethynyl.
  • thiophenylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a thiophenyl. Particular thiophenylalkenyl group is thiophenylethenyl.
  • thiophenylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a thiophenyl.
  • Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyl and thiophenylpropyl. More particular thiophenylalkyl group is thiophenylmethyl.
  • thiophenylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a thiophenyl. Particular thiophenylalkynyl group is thiophenylethynyl.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • salts may be prepared by addition of an inorganic base or an organic base to the free acid.
  • Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.
  • Particular pharmaceutically acceptable salts of compounds of formula (I) are the sodium and potassium salts.
  • “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo.
  • protecting group denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
  • Protecting groups can be removed at the appropriate point.
  • Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.
  • Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups.
  • Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.
  • uM means microMolar and is equivalent to the symbol ⁇ M.
  • the abbreviation uL means microliter and is equivalent to the symbol ⁇ L.
  • the abbreviation ug means microgram and is equivalent to the symbol ⁇ g.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
  • a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R 7 , R 8 and R 9 .
  • a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is phenylalkyl substituted with R 7 , R 8 and R 9 .
  • the present invention also relates to compounds according to formula (I) as described herein, wherein R 1 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R 10 , R 11 and R 12 .
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is phenyl substituted phenyl with R 10 , R 11 and R 12 .
  • R 2 is 4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl or 2-aminosulfonylpyridin-5-yl.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- or -C(O)-.
  • a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is -N-.
  • an embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)- or -S(O) 2 -.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-.
  • R 7 , R 8 and R 9 are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenyl substituted with one halogen, and wherein at least one of R 7 , R 8 and R 9 is not H.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 7 is alkoxy, haloalkoxy, halogen or phenyl substituted with one halogen.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 7 is haloalkoxy or halogen.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is H, halogen or alkylsulfonyl.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is H or halogen.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 9 is H.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 10 is aminosulfonyl.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 and R 12 are independently selected from H, alkyl and halogen.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 11 and R 12 are independently selected from H and halogen.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m and n are 1.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m, n, p and q are 1.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is 4-aminosulfonylphenyl and of formula (la).
  • the preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. (chiral) chromatography or crystallization. The substituents and indices used in the following description of the processes have the significance given herein.
  • amine 1 is reacted with a suitable chloroformate ester of formula R 1 -O-C(O)-Cl ( 2 ), or with an imidazole-1-carboxylate ester of formula ( 3 ), leading to a compound of formula (I) wherein Y is -OC(O)-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof
  • a base e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Chloroformate esters 2 are commercially available or can be synthesised from the corresponding alcohol of formula R 1 -OH, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene), as described in the literature.
  • phosgene or a phosgene equivalent e. g., diphosgene, triphosgene
  • Imidazole-1-carboxylate esters 3 are synthesised from the corresponding alcohols of formula R 1 -OH, by reaction with 1,1'-carbonyldiimidazole. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile. The imidazole-1-carboxylate esters 3 are typically not isolated but directly reacted with amines 1 as described above.
  • Alcohols of formula R 1 -OH are commercially available or can be produced by methods described herein or known in the art.
  • amine 1 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 1 -N(R 5 )-C(O)-Cl ( 4 ), or, in the case where R 5 is H, with an isocyanate of formula R 1 -NCO ( 5 ), leading to compounds of formula (I) wherein Y is -NR 5 C(O)-.
  • N-(Chlorocarbonyl)amines ( 4 ) are synthesised from the corresponding amines of formula R 1 -N(R 5 )H by reaction with phosgene or a phosgene equivalent, as described in the literature.
  • Isocyanates 5 are commercially available or can be prepared from the corresponding amines of formula R 1 -NH 2 , by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, 1,1'-carbonyldiimidazole) using conditions described in the literature.
  • phosgene or a phosgene equivalent e. g., diphosgene, triphosgene, 1,1'-carbonyldiimidazole
  • amine 1 is reacted with a suitable carboxylic acid of formula R 1 -COOH ( 6 ) leading to a compound of formula (I), wherein Y is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dich
  • Amine 1 can also be reacted with suitable acylating reagents such as acyl chlorides of formula R 1 -COCl ( 7 ) to lead to compounds of formula (I) wherein Y is -C(O)-.
  • suitable acylating reagents such as acyl chlorides of formula R 1 -COCl ( 7 ) to lead to compounds of formula (I) wherein Y is -C(O)-.
  • the reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • Carboxylic acids ( 6 ) and acyl halides ( 7 ) are commercially available or can be prepared as described herein or in the literature.
  • amine 1 is reacted with a suitable sulfonyl chloride of formula R 1 -SO 2 Cl ( 8 ), leading to compounds of formula (I) wherein Y is -S(O 2 )-.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Sulfonyl chlorides ( 8 ) are commercially available or can be synthesised as described herein or in the literature.
  • amine 1 is reacted with a suitable chloro-oxadiazole reagent of general formula 9 , or with oxadiazolone reagent 10 , leading to a compound of formula (I), wherein Y is
  • reaction is performed in the presence of a base, e. g., potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane at temperatures between 20°C and 150°C.
  • a base e. g., potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene
  • reaction is performed in the presence of a coupling agent, e. g. benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate and a base, e. g., diisopropylethylamine or 4-methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between 20°C and 100°C as described in the literature.
  • a coupling agent e. g. benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • a base e. g., diisopropylethylamine or 4-methylmorpholine
  • Oxadiazolones 10 are commercially available or can be produced as described in the literature.
  • Chloro-oxadiazoles 9 are commercially available or can be produced from the corresponding oxadiazolones, by reaction with a suitable halogenating reagent, e. g. phosphorus oxychloride and/or phosphorus pentachloride, at temperatures between 60°C and 120°C.
  • a suitable halogenating reagent e. g. phosphorus oxychloride and/or phosphorus pentachloride
  • reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane
  • Thiadiazolethiones 12 are commercially available or can be produced as described in the literature.
  • Halo-thiadiazoles 11 are commercially available or can be produced as described in the literature.
  • Amines of general formula 1 are synthesised from suitably protected precursors 13.
  • Suitable protective groups are tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • the deprotection of intermediates 13 can be performed using methods and reagents known in the art.
  • the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C in solvents such as methanol or ethanol.
  • a suitable catalyst such as palladium on activated charcoal
  • the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
  • a suitable acid e. g, hydrochloric acid or trifluoroacetic acid
  • a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
  • PG is a suitable protective group, e. g., tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • Intermediates 13A can be produced from amine precursors of general formula 14 by reaction with appropriate reagents, using methods known in the art.
  • alkylating agents of general formula X-CR 3 R 4 -R 2 ( 15 ) where X is a leaving group such as Cl, Br, I, or OSO 2 CH 3 , leading to 13A , wherein W is -CR 3 R 4 -.
  • This reaction is performed in a solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • amine 14 is reacted with aldehydes or ketones of general formula R 4 -C(O)-R 2 ( 16 ) in a reductive amination reaction, leading to 13A.
  • This reaction is performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • amine 14 is reacted with a suitable carboxylic acid of formula R 2 -COOH ( 17 ), leading to compounds of formula 13A, wherein W is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane
  • amine 14 is reacted with a suitable sulfonyl chloride of formula R 2 -SO 2 Cl ( 18 ), leading to compounds of formula 13A, wherein W is -S(O 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a base e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids 17, sulfonyl chlorides 18, and amines 22 are commercially available or can be synthesised as described in the literature or in the experimental section.
  • Intermediates 13 wherein A is C-H are represented by general formula 13B, wherein PG is a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • PG is a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • Compound 13B wherein W is -NR 6 -, is produced from ketone 19 by reaction with an amine of formula HN(R 6 )R 2 ( 20 ) in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane, or mixtures thereof, at temperatures between 0°C and 50°C.
  • a suitable reducing agent e. g. sodium borohydride or sodium triacetoxyborohydride
  • Ketones 19 and amines 20 are commercially available or can be prepared as described in the literature.
  • Compound 13B wherein W is -O- or -S-, is produced from alcohol 21 using methods and reagents known in the art.
  • alcohol 24 is reacted at room temperature with phenol HO-R 2 or thiophenol HS-R 2 in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g. diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene, dichloromethane, or tetrahydrofuran, leading to 13B, wherein W is -O- or -S-.
  • dialkylazodicarboxylate e. g. diisopropylazodicarboxylate or diethylazodicarboxylate
  • Compound 13B wherein W is -SO 2 -, is produced from compound 13B, wherein W is -S-, by oxidation with a suitable reagent, e. g., hydrogen peroxide or 3-chloroperbenzoic acid, in a solvent such as formic acid, acetic acid, or dichloromethane, at temperatures between 0°C and 50°C.
  • a suitable reagent e. g., hydrogen peroxide or 3-chloroperbenzoic acid
  • a solvent such as formic acid, acetic acid, or dichloromethane
  • Alcohols 21 are produced from ketones 19 using a suitable reducing agent, e. g., sodium borohydride, in a solvent such as methanol, at temperatures between 0°C and 50°C.
  • a suitable reducing agent e. g., sodium borohydride
  • Compounds of formula (I), wherein A is N can be produced from amine precursors of general formula 22 by reaction with appropriate reagents, using methods known in the art.
  • an amine of formula 22 is reacted with alkylating agents of general formula X-CR 3 R 4 -R 2 ( 15 ) where X is a leaving group such as Cl, Br, I, or OSO 2 CH 3 , leading to compounds of formula (I), wherein A is N and W is -CR 3 R 4 -.
  • This reaction is performed in a solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g., triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • an amine of formula 22 is reacted with aldehydes or ketones of general formula R 4 -C(O)-R 2 ( 16 ) in a reductive amination reaction, leading to compounds of formula (I) wherein A is N, W is -CR 3 R 4 -, R 4 is hydrogen, alkyl or cycloalkyl, and R 3 is H.
  • This reaction is performed in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • amine 22 is reacted with a suitable carboxylic acid of formula R 2 -COOH ( 17 ), leading to compounds of formula (I) wherein A is N and W is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as
  • amine 22 is reacted with a suitable sulfonyl chloride of formula R 2 -SO 2 Cl ( 18 ), leading to (I) wherein A is N and W is -S(O 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a base e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Amines 22 can be synthesised from their tert-butyl carbamate derivatives of formula 23 by carbamate deprotection.
  • the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at temperatures between 0°C and 30°C.
  • tert-Butyl carbamates 23 can be synthesised from amine precursors of formula 24 and appropriate reagents, using methods well known in the art.
  • an amine of formula 24 is reacted with a suitable chloroformate ester of formula R 1 -O-C(O)-Cl ( 2 ), or with an imidazole-1-carboxylate ester of formula ( 3 ), leading to compounds of formula 23 , wherein Y is -OC(O)-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a base e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of
  • an amine of formula 24 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 1 -N(R 5 )-C(O)-Cl ( 4 ) leading to compounds of formula 23 , wherein Y is - NR 5 C(O)-, or with an isocyanate of formula R 1 -NCO ( 5 ) leading to compounds of formula 23 , wherein Y is -NR 5 C(O)- and R 5 is H.
  • amine 24 is reacted with a suitable carboxylic acid of formula R 1 -COOH ( 6 ) leading to compounds of formula 23 , wherein Y is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotnazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichlor
  • Amine 24 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R 1 -COCl ( 7 ) to provide compounds of formula 23 , wherein Y is -C(O)-.
  • suitable acylating reagents such as acyl chlorides of formula R 1 -COCl ( 7 ) to provide compounds of formula 23 , wherein Y is -C(O)-.
  • the reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • amine 24 is reacted with a suitable sulfonyl chloride, of formula R 1 -SO 2 Cl ( 8 ), leading to compounds of formula 23 , wherein Y is -S(O 2 )-.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • amine 24 is reacted with a suitable chloro-oxadiazole reagent of general formula 9 , or with oxadiazolone reagent 10 , leading to compounds of formula 23 , wherein Y is
  • reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane
  • reaction is performed in the presence of a coupling agent, e. g., benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4-methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature).
  • a coupling agent e. g., benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • a base e. g. diisopropylethylamine or 4-methylmorpholine
  • amine 24 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is Cl or Br), or with thiadiazolethione reagent 12 , leading to compounds of formula 23 , wherein Y is
  • reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane
  • reaction is performed in a solvent such as ethanol or N,N-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
  • amine 24 is acylated with a haloalkanoyl halide, e. g., bromoacetyl chloride, in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at temperatures between -78°C and +20°C, leading to the corresponding haloalkanamide intermediate, which in the presence of a base, e. g.
  • a haloalkanoyl halide e. g., bromoacetyl chloride
  • a base e. g. triethylamine
  • a solvent such as dichloromethane or tetrahydrofuran
  • potassium carbonate or caesium carbonate in a solvent such as N,N-dimethylformamide undergoes a nucleophilic substitution reaction with a substituted phenol, leading to compounds of formula 28 , wherein Y is -C(O)- and R 1 is substituted phenoxyalkyl.
  • Amines of formula 24 are commercially available or can be produced as described in the literature or in the experimental section.
  • an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III); wherein R 1 , R 2 , A, W, m, n, p and q are as defined above, Y is -OC(O)-.
  • a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate
  • a solvent such as N,N-dimethylformamide
  • a base such as 4-methylmorpholine and at a temperature comprised between -78°C and reflux, particularly between -10°C and room temperature.
  • an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.
  • an object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
  • An object of the invention is a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD).
  • ESRD end-stage renal disease
  • this includes decreased creatinine clearance and decreased glomerular filtration rate, micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA
  • Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
  • Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • chronic asthma bronchiale chronic asthma bronchiale.
  • Further conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
  • iatrogenic drug-induced fibrosis etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (s
  • Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis), peripheral and/or autonomic (diabetic) neuropathies and the like.
  • Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like.
  • Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage.
  • Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis.
  • the compounds of formula (I) or their pharmaceutically acceptable salts can be used for the treatment or prophylaxis of organ or skin fibrosis.
  • the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.
  • the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis. In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.
  • Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
  • Ocular conditions include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
  • proliferative and non-proliferative (diabetic) retinopathy dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
  • AMD age-related macular degeneration
  • Metabolic conditions include, but are not limited to, obesity and diabetes.
  • the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cholestatic or non-cholestatic chronic pruritus.
  • the present invention also relates to a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • the present invention also relates to a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • the renal condition is selected from the group consisting of acute kidney injury, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection and chronic allograft nephropathy.
  • the renal condition is acute kidney injury.
  • the renal condition is chronic kidney disease.
  • the renal condition is diabetic nephropathy.
  • the renal condition is acute kidney transplant rejection.
  • the renal condition is chronic allograft nephropathy.
  • the liver condition is acute and chronic liver transplant rejection
  • the inflammatory condition is arthritis.
  • the condition of the nervous system is neuropathic pain.
  • the fibrotic disease is encapsulating peritonitis
  • the fibrotic disease is idiopathic pulmonary fibrosis.
  • the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
  • Autotaxin (ATX - ENPP2) cloning cDNA was prepared from commercial human hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length human ENPP2 ORF with or without a 3'-6xHis tag. These full length inserts were cloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 conforms to Swissprot entry Q13822, with or without the additional C-terminal 6xHis tag.
  • ATX Fermentation Recombinant protein was produced by large-scale transient transfection in 20 L controlled stirred tank bioreactors (Sartorius). During cell growth and transfection, temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1 and 30% DO, respectively.
  • FreeStyle 293-F cells (Invitrogen) were cultivated in suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as complexing agent.
  • ATX Purification 20 liter of culture supernatant were conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was first microfiltred through a 0.2 ⁇ m Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiSO 4 was added to a final concentration of 1 mM.
  • the cleared supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na 2 HPO 4 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN 3 .
  • the column was washed stepwise with the same buffer containing 20 mM , 40 mM and 50 mM imidazole, respectively.
  • the protein was subsequently eluted using a linear gradient to 0.5 M imidazole in 15 column volumes.
  • ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane.
  • the protein was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN 3 . Final yield of protein after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80°C.
  • ATX inhibition was measured by a fluorescence quenching assay using a specifically labeled substrate analogue (MR121 substrate).
  • MR121 substrate a specifically labeled substrate analogue
  • BOC and TBS protected 6-amino-hexanoic acid (R)-3-( ⁇ 2-[3-(2- ⁇ 2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy ⁇ -ethoxy)-propionylamino]-ethoxy ⁇ -hydroxy-phosphoryloxy)-2-hydroxy-propyl ester ( Ferguson et al., Org Lett 2006, 8 (10), 2023 ) was labeled with MR121 fluorophore ( CAS 185308-24-1 , 1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2',3'-i]phenoxazin-13-ium) on the free amine of the ethanolamine
  • Test compounds (10 mM stock in DMSO, 8 ⁇ L) were obtained in 384 well sample plates (Corning Costar #3655) and diluted with 8 ⁇ L DMSO. Row-wise serial dilutions were made by transferring 8 ⁇ L cpd solution to the next row up to row O. The compound and control solutions were mixed five times and 2 ⁇ L were transferred to 384 well assay plates (Corning Costar # 3702). Then, 15 ⁇ L of 41.7 nM ATX solution was added (30 nM final concentration), mixed five times and then incubated for 15 minutes at 30°C. 10 ⁇ L of MR121 substrate solution was added (1 ⁇ M final concentration), mixed 30 times and then incubated for 15 minutes at 30 °C.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
  • Acetyl chloride (8.7 mg, 110 ⁇ mol) was added at 0°C to a suspension of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.06; 40 mg, 92.1 ⁇ mol) and triethylamine (28.0 mg, 276 ⁇ mol) in dichloromethane (1 mL). The ice bath was removed, then after 90 min another portion of acetyl chloride (5.8 mg, 73 ⁇ mol) was added, then after another 2 h the reaction mixture was partitioned between dichloromethane and brine.
  • reaction mixture was heated at 80°C for 16 h, then another portion of sodium azide (24.3 mg, 374 ⁇ mol) and zinc bromide (21.0 mg, 93.4 ⁇ mol) was added, then after another 14 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol 4:1) afforded the title compound (46 mg, 51%). White foam, MS: 487.4 (M+H) + .
  • Step 1 (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(N-(methylsulfonyl)methylsulfonamido)-picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Step 2 (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Step 1 (3aR,6aS)-2-tert-Butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
  • Step 2 (3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride
  • Step 1 (3aR,8aS)-tert-butyl 6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydro-pyrrolo[3,4-d]azepine-2(1H)-carboxylate
  • Step 2 (E)-1-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)-phenyl)prop-2-en-1-one hydrochloride
  • Step 1 (3aS,6aS)-tert-Butyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Step 2 4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride (intermediate 4)

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Description

  • The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LPA) production and thus modulators of LPA levels and associated signaling, for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • Compounds that are capable of inhibiting ATX are described in WO 2010/112124 .
  • The present invention provides novel compounds of formula (I)
    Figure imgb0001
     wherein
    • R1
    is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R7, R8 and R9;
    R2
    is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted pyrrolyl and substituted thiophenyl are substituted with R10, R11 and R12;
    Y
    is -OC(O)-, -NR5C(O)-, -C(O)-, -S(O)2-,
    Figure imgb0002
    A
    is -N- or CH-;
    W
    is -O-, -S-, -NR6-, -C(O)-, -S(O)2-, or -CR3R4-;
    R3 and R4
    are independently selected from H, halogen, alkyl and cycloalkyl;
    R5 and R6
    are independently selected from H, alkyl and cycloalkyl;
    R7, R8 and R9
    are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy, wherein at least one of R7, R8 and R9 is not H;
    R10
    is substituted aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
    R11 and R12
    are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and haloalkyl;
    m, n, p and q
    are independently selected from 1 or 2;
    or pharmaceutically acceptable salts.
  • Autotaxin (ATX) is a secreted enzyme also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D that is important for converting lysophosphatidyl choline (LPC) to the bioactive signaling molecule lysophosphatidic acid (LPA). It has been shown that plasma LPA levels are well correlated with ATX activity and hence ATX is believed to be an important source of extracellular LPA. Early experiments with a prototype ATX inhibitor have shown that such a compound is able to inhibit the LPA synthesizing activity in mouse plasma. Work conducted in the 1970s and early 1980s has demonstrated that LPA can elicit a wide range of cellular responses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis and others. LPA mediates its effects via signaling to several G protein coupled receptors (GPCRs); the first members were originally denoted Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-1(vzg-1) but are now called LPA receptors. The prototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23, LPA5/GPR92 and LPA6/p2Y5 have been described that are more closely related to nucleotide-selective purinergic receptors than to the prototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in a large range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression and altered responses to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.
  • In accordance with the invention, the compounds of formula (I) or their pharmaceutically acceptable salts can be used for the treatment or prophylaxis of diseases, disorders or conditions that are associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).
  • The compounds of formula (I) or their pharmaceutically acceptable salts herein inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling. Autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. The ATX-LPA axis has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular conditions, metabolic conditions such as obesity and/or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as acute and chronic organ transplant rejection.
  • Objects of the present invention are the compounds of formula (I) and their aforementioned salts and their use as therapeutically active substances, a process for the manufacture of the said compounds, pharmaceutical compositions, medicaments containing the said compounds or their pharmaceutically acceptable salts, the said compounds or their pharmaceutically acceptable salts for use in the treatment or prophylaxis of disorders or conditions that are associated with the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA), particularly in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and-chronic organ transplant rejection, and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • The term "alkenyl" denotes a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenyl group is ethenyl.
  • The term "alkoxy" denotes a group of the formula -O-R', wherein R' is an alkyl group. Examples of alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy group include isopropoxy.
  • The term "alkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy group include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.
  • The term "alkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.
  • The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl and isopropoxymethyl. Particular alkoxyalkyl group include include methoxymethyl, methoxyethyl and isopropoxymethyl.
  • The term "alkoxycarbonyl" denotes a group of the formula -C(O)-R', wherein R' is an alkoxy group. Examples of alkoxycarbonyl groups include groups of the formula -C(O)-R', wherein R' is methoxy or ethoxy. Particular alkoxycarbonyl group include groups of the formula -C(O)-R', wherein R' is methoxy.
  • The term "alkoxyhaloalkyl" denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl and ethoxytrifluoropropyl.
  • The term "alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl group is methyl.
  • The term "alkylcarbonyl" denotes a group of the formula -C(O)-R', wherein R' is an alkyl group. Examples of alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is methyl or ethyl. Particular alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is methyl.
  • The term "alkylcarbonylamino" denotes a group of the formula -NH-C(O)-R', wherein R' is an alkyl group. Examples of alkylcarbonylamino groups include groups of the formula -NH-C(O)-R', wherein R' is methyl or ethyl. Particular a alkylcarbonylamino groups include groups of the formula -NH-C(O)-R', wherein R' is methyl.
  • The term "alkylsulfanyl" denotes a group of the formula -S-R', wherein R' is an alkyl group. Examples of alkylsulfanyl groups include groups of the formula -S-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfanyl groups include group of the formula -S-R', wherein R' is methyl.
  • The term "alkylsulfinyl" denotes a group of the formula -S(O)-R', wherein R' is an alkyl group. Examples of alkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfinyl groups include group of the formula -S(O)-R', wherein R' is methyl.
  • The term "alkylsulfonyl" denotes a group of the formula -S(O)2-R', wherein R' is an alkyl group. Examples of alkylsulfonyl groups include groups of the formula -S(O)2-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfonyl groups include group of the formula -S(O)2-R', wherein R' is methyl.
  • The term "alkylsulfonylamino" denotes a group of the formula -NH-S(O)2-R', wherein R' is an alkyl group. Examples of alkylsulfonylamino groups include groups of the formula -NH-S(O)2-R', wherein R' is methyl or ethyl. Particular a alkylsulfonylamino groups include groups of the formula -NH-S(O)2-R', wherein R' is methyl.
  • The term "amino" denotes a -NH2 group.
  • The term "aminoalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aminogroup. Examples of aminoalkyl include aminomethyl, aminoethyl, amino-1-methyl-ethyl, aminopropyl, aminomethylpropyl and aminopropyl. Particular examples are aminomethyl and haminoethyl.
  • The term "aminosulfonyl" denotes a -S(O)2-NH2 group.
  • The term "carbonyl" denotes a -C(O)- group.
  • The term "carboxy" denotes a -COOH group.
  • The term "cyano" denotes a -C≡N group.
  • The term "cycloalkoxy" denotes a group of the formula -O-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.
  • The term "cycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of cycloalkoxyalkyl groups include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
  • The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.
  • The term "cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.
  • The term "cycloalkylalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.
  • The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and adamantanylethyl. Particular examples of cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and adamantanylethyl. Further particular examples cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl, adamentanylmethyl and adamantanylethyl.
  • The term "cycloalkylcarbonyl"of the formula -C(O)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is cyclopropyl.
  • The term "cycloalkylsulfanyl" denotes a group of the formula -S-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is cyclopropyl.
  • The term "cycloalkylsulfinyl" denotes a group of the formula -S(O)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is cyclopropyl.
  • The term "cycloalkylsulfonyl" denotes a group of the formula -S(O)2-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfonyl groups include groups of the formula -S(O)2-R', wherein R' is cyclopropyl.
  • The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy group is trifluoromethoxy.
  • The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms. The term "perhaloalkyl" denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group is trifluoromethyl.
  • The term "haloalkylsulfanyl" denotes a group of the formula -S-R', wherein R' is a haloalkyl group. Examples of haloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is trifluoromethyl.
  • The term "haloalkylsulfinyl" denotes a group of the formula -S(O)-R', wherein R' is a haloalkyl group. Examples of haloalkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is trifluoromethyl.
  • The term "haloalkylsulfonyl" denotes a group of the formula -S(O)2-R', wherein R' is a haloalkyl group. Examples of haloalkylsulfonyl groups include groups of the formula -S(O)2-R', wherein R' is trifluoromethyl.
  • The term "halogen" and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro and fluoro.
  • The term "hydroxy" denotes a -OH group.
  • The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.
  • The term "hydroxyhaloalkyl" denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an hydroxy group. Exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.
  • The term "naphthylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a naphthynaphthyl. Particular naphthylalkenyl group is naphytylethenyl.
  • The term "naphthylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a naphthyl. Particular naphthylalkyl groups are naphthylmethyl, naphthylethyl and naphthylpropyl.
  • The term "naphthyloxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a naphthyloxy group. Exemplary naphthyloxyalkyl groups include naphthyloxymethyl, naphthyloxyethyl and naphthyloxypropyl.
  • The term "phenoxy" denotes a group of the formula -O-R', wherein R' is a phenyl.
  • The term "phenoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a phenoxy group. Exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyl and phenoxypropyl. Particular alkoxyalkyl group is phenoxymethyl.
  • The term "phenylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a phenyl. Particular phenylalkenyl group is phenylethenyl.
  • The term "phenylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a phenyl. Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl. Further particular phenylalkyl group is benzyl.
  • The term "phenylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a phenyl. Particular phenylalkynyl group is phenylethynyl.
  • The term "phenylcyloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced a phenyl. Particular phenylcycloalkyl group is phenylcyclopropyl.
  • The term "pyridinylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a pyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.
  • The term "pyridinylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a pyridinyl. Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl and pyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.
  • The term "pyridinylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a pyridinyl. Particular pyridinylalkynyl group is pyridinylethynyl.
  • The term "thiophenylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a thiophenyl. Particular thiophenylalkenyl group is thiophenylethenyl.
  • The term "thiophenylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a thiophenyl. Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyl and thiophenylpropyl. More particular thiophenylalkyl group is thiophenylmethyl.
  • The term "thiophenylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a thiophenyl. Particular thiophenylalkynyl group is thiophenylethynyl.
  • The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the sodium and potassium salts.
  • "Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo.
  • The term "protecting group" (PG) denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.
  • The abbreviation uM means microMolar and is equivalent to the symbol µM.
  • The abbreviation uL means microliter and is equivalent to the symbol µL.
  • The abbreviation ug means microgram and is equivalent to the symbol µg.
  • The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration.
  • Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
  • A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R7, R8 and R9.
  • A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is phenylalkyl substituted with R7, R8 and R9.
  • In a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is 3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl or 4-trifluoromethoxyphenylethyl.
  • The present invention also relates to compounds according to formula (I) as described herein, wherein R1 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R10, R11 and R12.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is phenyl substituted phenyl with R10, R11 and R12.
  • Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is 4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl or 2-aminosulfonylpyridin-5-yl.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- or -C(O)-.
  • A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is -N-.
  • Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)- or -S(O)2-.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7, R8 and R9 are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenyl substituted with one halogen, and wherein at least one of R7, R8 and R9 is not H.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7 is alkoxy, haloalkoxy, halogen or phenyl substituted with one halogen.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7 is haloalkoxy or halogen.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is H, halogen or alkylsulfonyl.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is H or halogen.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 is H.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R10 is aminosulfonyl.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R11 and R12 are independently selected from H, alkyl and halogen.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R11 and R12 are independently selected from H and halogen.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m and n are 1.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m, n, p and q are 1.
  • A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is 4-aminosulfonylphenyl and of formula (la).
    Figure imgb0003
  • Particular examples of compounds of formula (I) as described herein are selected from
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • 4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;
    • (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy benzyl ester;
    • (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • 4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5 -methanesulfonyl-benzyl ester;
    • (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
    • (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • 4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-{(3aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-[(3aS,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;
    • (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    • (-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    and pharmaceutically acceptable salts thereof.
  • Also particular examples of compounds of formula (I) as described herein are selected from
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • 4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;
    • (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy benzyl ester;
    • (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • 4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid;
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5 -methanesulfonyl-benzyl ester;
    • (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
    • (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • 4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-{(3aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-[(3aS,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    • 4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • 4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;
    • (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    • (-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    • (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • 5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonic acid amide;
    • 5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;
    • (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;
    • (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester;
    • (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;and pharmaceutically acceptable salts thereof.
  • Further particular examples of compounds of formula (I) as described herein are selected from
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • 4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    and pharmaceutically acceptable salts thereof.
  • Also further particular examples of compounds of formula (I) as described herein are selected from
    • (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    • (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    • 4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    • (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;
    and pharmaceutically acceptable salts thereof. Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.
  • The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. (chiral) chromatography or crystallization. The substituents and indices used in the following description of the processes have the significance given herein.
  • Compounds of general formula (I) can be synthesised from amine precursor 1 and appropriate reagents, using methods well known in the art.
    Figure imgb0004
  • For instance, amine 1 is reacted with a suitable chloroformate ester of formula R1-O-C(O)-Cl (2), or with an imidazole-1-carboxylate ester of formula (3), leading to a compound of formula (I) wherein Y is -OC(O)-.
    Figure imgb0005
  • The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Chloroformate esters 2 are commercially available or can be synthesised from the corresponding alcohol of formula R1-OH, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene), as described in the literature.
  • Imidazole-1-carboxylate esters 3 are synthesised from the corresponding alcohols of formula R1-OH, by reaction with 1,1'-carbonyldiimidazole. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile. The imidazole-1-carboxylate esters 3 are typically not isolated but directly reacted with amines 1 as described above.
  • Alcohols of formula R1-OH are commercially available or can be produced by methods described herein or known in the art.
  • Alternatively, amine 1 is reacted with a suitable N-(chlorocarbonyl)amine of formula R1-N(R5)-C(O)-Cl (4), or, in the case where R5 is H, with an isocyanate of formula R1-NCO (5), leading to compounds of formula (I) wherein Y is -NR5C(O)-.
  • N-(Chlorocarbonyl)amines (4) are synthesised from the corresponding amines of formula R1-N(R5)H by reaction with phosgene or a phosgene equivalent, as described in the literature.
  • Isocyanates 5 are commercially available or can be prepared from the corresponding amines of formula R1-NH2, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, 1,1'-carbonyldiimidazole) using conditions described in the literature.
  • Alternatively, amine 1 is reacted with a suitable carboxylic acid of formula R1-COOH (6) leading to a compound of formula (I), wherein Y is -C(O)-. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Amine 1 can also be reacted with suitable acylating reagents such as acyl chlorides of formula R1-COCl (7) to lead to compounds of formula (I) wherein Y is -C(O)-. The reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • Carboxylic acids (6) and acyl halides (7) are commercially available or can be prepared as described herein or in the literature.
  • Alternatively, amine 1 is reacted with a suitable sulfonyl chloride of formula R1-SO2Cl (8), leading to compounds of formula (I) wherein Y is -S(O2)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Sulfonyl chlorides (8) are commercially available or can be synthesised as described herein or in the literature.
  • Alternatively, amine 1 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to a compound of formula (I), wherein Y is
    Figure imgb0006
    Figure imgb0007
  • In the case where compounds of formula (I) are produced from amine 1 and chloro-oxadiazole 9, the reaction is performed in the presence of a base, e. g., potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane at temperatures between 20°C and 150°C.
  • In the case where compounds of formula (I) are produced from amine 1 and oxadiazolone 10, the reaction is performed in the presence of a coupling agent, e. g. benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate and a base, e. g., diisopropylethylamine or 4-methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between 20°C and 100°C as described in the literature.
  • Oxadiazolones 10 are commercially available or can be produced as described in the literature.
  • Chloro-oxadiazoles 9 are commercially available or can be produced from the corresponding oxadiazolones, by reaction with a suitable halogenating reagent, e. g. phosphorus oxychloride and/or phosphorus pentachloride, at temperatures between 60°C and 120°C.
  • Alternatively, amine 1 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X = Cl or Br), or with thiadiazolethione reagent 12, leading to compounds of (I) wherein Y is
    Figure imgb0008
    Figure imgb0009
  • In the case where compounds of formula (I) are produced from amine 1 and halo-thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • In the case where compounds of formula (I) are produced from amine 1 and thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or N,N-dimethylformamide at temperatures between 20°C and 100°C as described in the literature.
  • Thiadiazolethiones 12 are commercially available or can be produced as described in the literature.
  • Halo-thiadiazoles 11 are commercially available or can be produced as described in the literature.
  • Amines of general formula 1 are synthesised from suitably protected precursors 13.
    Figure imgb0010
  • Suitable protective groups (PG) are tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl. The deprotection of intermediates 13 can be performed using methods and reagents known in the art.
  • For instance, in the case where PG is optionally substituted benzyloxycarbonyl, the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C in solvents such as methanol or ethanol.
  • Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
  • Intermediates 13, wherein A is N are represented by general structure 13A.
    Figure imgb0011
  • PG is a suitable protective group, e. g., tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • Intermediates 13A can be produced from amine precursors of general formula 14 by reaction with appropriate reagents, using methods known in the art.
    Figure imgb0012
  • For instance, 14 is reacted with alkylating agents of general formula X-CR3R4-R2 (15) where X is a leaving group such as Cl, Br, I, or OSO2CH3, leading to 13A, wherein W is -CR3R4-. This reaction is performed in a solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • Alternatively, for compounds of formula 13A, wherein W is -CR3R4-, R4 is hydrogen, alkyl or cycloalkyl, and R3 is H, amine 14 is reacted with aldehydes or ketones of general formula R4-C(O)-R2 (16) in a reductive amination reaction, leading to 13A. This reaction is performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • Alternatively, amine 14 is reacted with a suitable carboxylic acid of formula R2-COOH (17), leading to compounds of formula 13A, wherein W is -C(O)-. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between - 40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Alternatively, amine 14 is reacted with a suitable sulfonyl chloride of formula R2-SO2Cl (18), leading to compounds of formula 13A, wherein W is -S(O2)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids 17, sulfonyl chlorides 18, and amines 22 are commercially available or can be synthesised as described in the literature or in the experimental section.
  • Intermediates 13 wherein A is C-H are represented by general formula 13B, wherein PG is a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
    Figure imgb0013
  • Compound 13B, wherein W is -NR6-, is produced from ketone 19 by reaction with an amine of formula HN(R6)R2 (20) in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane, or mixtures thereof, at temperatures between 0°C and 50°C.
    Figure imgb0014
  • Ketones 19 and amines 20 are commercially available or can be prepared as described in the literature.
  • Compound 13B, wherein W is -O- or -S-, is produced from alcohol 21 using methods and reagents known in the art.
    Figure imgb0015
  • For instance, alcohol 24 is reacted at room temperature with phenol HO-R2 or thiophenol HS-R2 in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g. diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene, dichloromethane, or tetrahydrofuran, leading to 13B, wherein W is -O- or -S-.
  • Alternatively, conversion of alcohol 21 to the corresponding methanesulfonate using methanesulfonyl chloride in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at temperatures between -20°C and +30°C, and treatment of the methanesulfonate intermediate with phenol HO-R2 or thiophenol HS-R2 in the presence of a base, e. g., potassium carbonate, in a solvent such as N,N-dimethylformamide or acetonitrile, at temperatures between 20°C and 100°C, leads to 13B, wherein W is -O- or -S-.
  • Compound 13B, wherein W is -SO2-, is produced from compound 13B, wherein W is -S-, by oxidation with a suitable reagent, e. g., hydrogen peroxide or 3-chloroperbenzoic acid, in a solvent such as formic acid, acetic acid, or dichloromethane, at temperatures between 0°C and 50°C.
  • Alcohols 21 are produced from ketones 19 using a suitable reducing agent, e. g., sodium borohydride, in a solvent such as methanol, at temperatures between 0°C and 50°C.
  • Compounds of formula (I), wherein A is N can be produced from amine precursors of general formula 22 by reaction with appropriate reagents, using methods known in the art.
    Figure imgb0016
  • For instance, an amine of formula 22 is reacted with alkylating agents of general formula X-CR3R4-R2 (15) where X is a leaving group such as Cl, Br, I, or OSO2CH3, leading to compounds of formula (I), wherein A is N and W is -CR3R4-. This reaction is performed in a solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g., triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • Alternatively, an amine of formula 22 is reacted with aldehydes or ketones of general formula R4-C(O)-R2 (16) in a reductive amination reaction, leading to compounds of formula (I) wherein A is N, W is -CR3R4-, R4 is hydrogen, alkyl or cycloalkyl, and R3 is H. This reaction is performed in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • Alternatively, amine 22 is reacted with a suitable carboxylic acid of formula R2-COOH (17), leading to compounds of formula (I) wherein A is N and W is -C(O)-. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between - 40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Alternatively, amine 22 is reacted with a suitable sulfonyl chloride of formula R2-SO2Cl (18), leading to (I) wherein A is N and W is -S(O2)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Amines 22 can be synthesised from their tert-butyl carbamate derivatives of formula 23 by carbamate deprotection. The deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at temperatures between 0°C and 30°C.
    Figure imgb0017
     tert-Butyl carbamates 23 can be synthesised from amine precursors of formula 24 and appropriate reagents, using methods well known in the art.
    Figure imgb0018
  • For instance, an amine of formula 24 is reacted with a suitable chloroformate ester of formula R1-O-C(O)-Cl (2), or with an imidazole-1-carboxylate ester of formula (3), leading to compounds of formula 23, wherein Y is -OC(O)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Alternatively, an amine of formula 24 is reacted with a suitable N-(chlorocarbonyl)amine of formula R1-N(R5)-C(O)-Cl (4) leading to compounds of formula 23, wherein Y is - NR5C(O)-, or with an isocyanate of formula R1-NCO (5) leading to compounds of formula 23, wherein Y is -NR5C(O)- and R5 is H.
  • Alternatively, amine 24 is reacted with a suitable carboxylic acid of formula R1-COOH (6) leading to compounds of formula 23, wherein Y is -C(O)-. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotnazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Amine 24 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R1-COCl (7) to provide compounds of formula 23, wherein Y is -C(O)-. The reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • Alternatively, amine 24 is reacted with a suitable sulfonyl chloride, of formula R1-SO2Cl (8), leading to compounds of formula 23, wherein Y is -S(O2)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Alternatively, amine 24 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to compounds of formula 23, wherein Y is
    Figure imgb0019
  • In the case where 23 is produced from amine 24 and chloro-oxadiazole 9, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • In the case where 23 is produced from amine 24 and oxadiazolone 10, the reaction is performed in the presence of a coupling agent, e. g., benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4-methylmorpholine, in a solvent such as N,N-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature).
  • Alternatively, amine 24 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is Cl or Br), or with thiadiazolethione reagent 12, leading to compounds of formula 23, wherein Y is
    Figure imgb0020
  • In the case where 23 is produced from amine 24 and halo-thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • In the case where 23 is produced from amine 24 and thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or N,N-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
  • Alternatively, amine 24 is acylated with a haloalkanoyl halide, e. g., bromoacetyl chloride, in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or tetrahydrofuran, at temperatures between -78°C and +20°C, leading to the corresponding haloalkanamide intermediate, which in the presence of a base, e. g. potassium carbonate or caesium carbonate, in a solvent such as N,N-dimethylformamide undergoes a nucleophilic substitution reaction with a substituted phenol, leading to compounds of formula 28, wherein Y is -C(O)- and R1 is substituted phenoxyalkyl.
  • Amines of formula 24 are commercially available or can be produced as described in the literature or in the experimental section.
  • Also an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);
    Figure imgb0021
     wherein R1, R2, A, W, m, n, p and q are as defined above, Y is -OC(O)-.
  • In particular, in the presence of a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, in a solvent such as N,N-dimethylformamide, in the presence of a base such as 4-methylmorpholine and at a temperature comprised between -78°C and reflux, particularly between -10°C and room temperature.
  • Also an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.
  • Likewise an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
  • An object of the invention is a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD). In more detail, this includes decreased creatinine clearance and decreased glomerular filtration rate, micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides / systemic diseases as well as acute and chronic kidney transplant rejection.
  • Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
  • Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
  • Further conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
  • Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis), peripheral and/or autonomic (diabetic) neuropathies and the like.
  • Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like.
  • Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage.
  • Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis.
  • In a particular embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts can be used for the treatment or prophylaxis of organ or skin fibrosis.
  • In another embodiment, the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.
  • In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
    In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.
  • Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
  • Ocular conditions include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
  • Metabolic conditions include, but are not limited to, obesity and diabetes.
  • In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cholestatic or non-cholestatic chronic pruritus.
  • The present invention also relates to a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • The present invention also relates to a compound according to formula (I) as described herein for use in the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • In a particular embodiment, the renal condition is selected from the group consisting of acute kidney injury, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection and chronic allograft nephropathy.
  • In another particular embodiment, the renal condition is acute kidney injury.
  • In another particular embodiment, the renal condition is chronic kidney disease.
  • In a further particular embodiment, the renal condition is diabetic nephropathy.
  • In another particular embodiment, the renal condition is acute kidney transplant rejection.
  • In another particular embodiment, the renal condition is chronic allograft nephropathy.
  • In a particular embodiment, the liver condition is acute and chronic liver transplant rejection
  • In a particular embodiment, the inflammatory condition is arthritis.
  • In a particular embodiment, the condition of the nervous system is neuropathic pain.
  • In another embodiment, the fibrotic disease is encapsulating peritonitis
  • In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.
  • In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
  • Also an embodiment of the present invention are compounds of formula (I) as described herein, when manufactured according to any one of the described processes.
    • Assay procedures PRODUCTION OF HUMAN FULL LENGTH ATX, WITH AND WITHOUT HIS TAG
  • Autotaxin (ATX - ENPP2) cloning: cDNA was prepared from commercial human hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length human ENPP2 ORF with or without a 3'-6xHis tag. These full length inserts were cloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 conforms to Swissprot entry Q13822, with or without the additional C-terminal 6xHis tag.
  • ATX Fermentation: Recombinant protein was produced by large-scale transient transfection in 20 L controlled stirred tank bioreactors (Sartorius). During cell growth and transfection, temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1 and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultivated in suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as complexing agent. Cells were fed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 h post-transfection and harvested at 96 h post-transfection. Expression was analyzed by Western Blot, enzymatic assay and/or analytical IMAC chromatography. After cooling the cell suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of supernatant was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.
  • ATX Purification: 20 liter of culture supernatant were conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was first microfiltred through a 0.2 µm Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiSO4 was added to a final concentration of 1 mM. The cleared supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3. The column was washed stepwise with the same buffer containing 20 mM , 40 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using a linear gradient to 0.5 M imidazole in 15 column volumes. ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. The protein was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3. Final yield of protein after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80°C.
    • HUMAN ATX ENZYME INHIBITION ASSAY
  • ATX inhibition was measured by a fluorescence quenching assay using a specifically labeled substrate analogue (MR121 substrate). To obtain this MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid (R)-3-({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionylamino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propyl ester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled with MR121 fluorophore (CAS 185308-24-1, 1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2',3'-i]phenoxazin-13-ium) on the free amine of the ethanolamine side and then, after deprotection, subsequently with tryptophan on the side of the aminohexanoic acid.
  • Assay working solutions were made as follows:
    • Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.01% Triton-X-100, pH 8.0;
    • ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3), diluted to 1.4 - 2.5x final concentration in assay buffer;
    • MR121 substrate solution: MR121 substrate stock solution (800 µM MR121 substrate in DMSO), diluted to 2 - 5x final concentration in assay buffer.
  • Test compounds (10 mM stock in DMSO, 8 µL) were obtained in 384 well sample plates (Corning Costar #3655) and diluted with 8 µL DMSO. Row-wise serial dilutions were made by transferring 8 µL cpd solution to the next row up to row O. The compound and control solutions were mixed five times and 2 µL were transferred to 384 well assay plates (Corning Costar # 3702). Then, 15 µL of 41.7 nM ATX solution was added (30 nM final concentration), mixed five times and then incubated for 15 minutes at 30°C. 10 µL of MR121 substrate solution was added (1µM final concentration), mixed 30 times and then incubated for 15 minutes at 30 °C. Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: vision multimode reader); light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630/690 nm) and IC50 values were calculated from these readouts.
  • IC50 values for the examples of this inventioan are given in the table below:
    Figure imgb0022
    Figure imgb0023
  • Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have IC50 values between 0.00001 µM and 1000 µM, particular compounds have IC50 values between 0.0005 µM and 500 µM, further particular compounds have IC50 values between 0.0005 µM and 50 µM, more particular compounds have IC50 values between 0.0005 µM and 5 µM. These results have been obtained by using the enzymatic assay described above.
  • The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided preferably into 1-3 individual doses, which can consist, for example, of the same amounts, should it be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.
  • The invention is illustrated hereinafter by Examples, which have no limiting character.
  • In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
    • Examples
  • All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.
  • Abbreviations: aq. = aqueous; CAS-RN = Chemical Abstracts Service Registry Number; HPLC = high performance liquid chromatography; MS = mass spectrum; sat. = saturated
    • Example 1 (3aR,6aS)-3,5-Dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0024
  • To a solution of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1; 40 mg, 114 µmol), 4-methylmorpholine (57.5 mg, 569 µmol) and 4-(N-methylsulfamoyl)benzoic acid (24.5 mg, 114 µmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (43.3 mg, 114 µmol) at 0°C, then the reaction mixture was allowed to reach room temperature over 16 h. After partitioning between ethyl acetate and aq. sat. sodium hydrogen carbonate solution the organic layer was washed with water and brine, dried over magnesium sulfate filtered and evaporated. Chromatography (silica gel; ethyl acetate-methanol gradient) afforded the title compound (58 mg, 99%). White foam, MS: 512.3 (M+H)+.
  • The following examples were prepared according to example 1, replacing (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride by the appropriate amine and 4-(N-methylsulfamoyl)benzoic acid by the appropriate carboxylic acid.
    Ex. Systematic Name Amine / Carboxylic acid MS, m/e
    1.01 (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 5-hydroxypicolinic acid 436.2 (M+H)+
    Figure imgb0025
    1.02 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 4-hydroxybenzoic acid 435.2 (M+H)+
    Figure imgb0026
    1.03 trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (3aS,7aS)-3,5-dichlorobenzyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate hydrochloride (intermediate 1.1) / 4-sulfamoylbenzoic acid 512.5 (M+H)+
    Figure imgb0027
    1.04 (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 5-sulfamoy lthiophene- 2-carboxylic acid 504.3 (M+H)+
    Figure imgb0028
    1.05 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 4-sulfamoylbenzoic acid 498.3 (M+H)+
    Figure imgb0029
    1.06 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 4-aminobenzoic acid 434.4 (M+H)+
    Figure imgb0030
    1.07 (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) /5-aminopicolinic acid hydrochloride 435.4 (M+H)+
    Figure imgb0031
    1.08 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 4-cyanobenzoic acid 444.2 (M+H)+
    Figure imgb0032
    1.09 (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1) / 4-(methoxycarbonyl)-benzoic acid 477.2 (M+H)+
    Figure imgb0033
    1.10 4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide (E)-1-((3aR,8aS)-octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phe nyl)prop-2-en-1-one hydrochloride (intermediate 2) / 4-sulfamoylbenzoic acid 538.5 (M+H)+
    Figure imgb0034
    1.11 (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 3-fluoro-4-sulfamoyl-benzoic acid (CAS-RN 244606-37-9) 532.5 (M+H)+
    Figure imgb0035
    1.12 (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 6-oxo-1,6-dihydropyridine-3 - carboxylic acid 452.5 (M+H)+
    Figure imgb0036
    1.13 (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 5-sulfamoy lpicolinic acid (CAS-RN 1308677-67-9) 515.5 (M+H)+
    Figure imgb0037
    1.14 (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 1-methyl-4-sulfamoyl-1H-pyrrole-2-carboxylic acid (CAS-RN 878218-38-3) 517.5 (M+H)+
    Figure imgb0038
    1.15 (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 1-methyl-5-sulfamoyl-1H-pyrrole-2-carboxylic acid (CAS-RN 306936-62-9) 517.5 (M+H)+
    Figure imgb0039
    1.16 (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 6-sulfamoy lnicotinic acid (CAS-RN 285135-56-0) 515.6 (M+H)+
    Figure imgb0040
    1.17 (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3 aS, 6aS)- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 5-hydroxypicolinic acid 452.4 (M+H)+
    Figure imgb0041
    1.18 (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3 aS, 6aS)- hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 4-hydroxybenzoic acid 451.4 (M+H)+
    Figure imgb0042
    1.19 (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2) / 2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0) 530.3 (M-H)
    Figure imgb0043
    1.20 5-{(3aR,6aR)-5-[3-(4-trifluoromethoxyphenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonic acid amide 1-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-one dihydrochloride (intermediate 2.2) / 6-sulfamoylnicotinic acid (CAS-RN 285135-56-0) 513.3 (M+H)+
    Figure imgb0044
    1.21 5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)pyridine-2-sulfonamide (4-ethoxyquinolin-2-yl)((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (intermediate 2.1) / 6-sulfamoylnicotinic acid (CAS-RN 285135-56-0) 496.2 (M+H)+
    Figure imgb0045
    1.22 (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester (3aS,6aS)-4-cyano-2-pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3) / 3-fluoro-4-sulfamoylbenzoic acid (CAS-RN 244606-37-9) 570.3 (M-H)
    Figure imgb0046
    1.23 (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester (3aS,6aS)-4-cyano-2-pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3) / 6-sulfamoylnicotinic acid (CAS-RN 285135-56-0) 553.3 (M-H)
    Figure imgb0047
    1.24 (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester (3aS,6aS)-4-cyano-2-pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3) / 4-sulfamoylbenzoic acid 552.3 (M-H)
    Figure imgb0048
    1.25 (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester (3aS,6aS)-4-cyano-2-pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3) / 2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0) 570.4 (M-H)
    Figure imgb0049
    1.26 (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester (3aS,6aS)-4-cyano-2-pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3) / 5-sulfamoylpicolinic acid (CAS-RN 1308677-67-9) 553.3 (M-H)
    Figure imgb0050
    • Example 2 (3aR,6aS)-3,5-Dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0051
  • Acetyl chloride (8.7 mg, 110 µmol) was added at 0°C to a suspension of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.06; 40 mg, 92.1 µmol) and triethylamine (28.0 mg, 276 µmol) in dichloromethane (1 mL). The ice bath was removed, then after 90 min another portion of acetyl chloride (5.8 mg, 73 µmol) was added, then after another 2 h the reaction mixture was partitioned between dichloromethane and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; ethyl acetate-methanol gradient) produced the title compound (27 mg, 61%). White foam, MS: 476.4 (M+H)+.
    • Example 2.1 (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0052
  • The title compound was produced in analogy to example 2, replacing (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.07). White solid, MS: 477.4 (M+H)+.
    • Example 3 (3aR,6aS)-3,5-Dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0053
  • To a suspension of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1; 50 mg, 142 µmol) and pyridine (112 mg, 1.42 mmol) in tetrahydrofuran (1 mL) was added a solution of 4-sulfamoylbenzene-1-sulfonyl chloride (32.7 mg, 128 µmol) in tetrahydrofuran (1 mL) at 0°C, then the reaction mixture was stirred at room temperature for 16 h. After partitioning between ethyl acetate and sat. aq. sodium hydrogencarbonate solution, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in ethyl acetate to produce the title compound (45 mg, 59%). Light yellow solid, MS: 532.1 (M-H)-.
    • Example 4 (3aR,6aS)-3,5-Dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0054
  • To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.08; 83 mg, 187 µmol) in 2-propanol (4 mL) and water (5 mL) was added sodium azide (24.3 mg, 374 µmol) and zinc bromide (21.0 mg, 93.4 µmol). The reaction mixture was heated at 80°C for 16 h, then another portion of sodium azide (24.3 mg, 374 µmol) and zinc bromide (21.0 mg, 93.4 µmol) was added, then after another 14 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol 4:1) afforded the title compound (46 mg, 51%). White foam, MS: 487.4 (M+H)+.
    • Example 5 4-((3aR,6aS)-5-((3,5-Dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid
  • Figure imgb0055
  • To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.09; 82 mg, 172 µmol) in tetrahydrofuran (1.5 mL) was added 2 M aq. sodium hydroxide solution (515 µl, 1.03 mmol). The reaction mixture was stirred at room temperature for 2 h, then heated at 50°C for 3 h, then partitioned between ethyl acetate and 1 M aq. hydrochloric acid solution. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (74 mg, 93%). White solid, MS: 463.6 (M-H)-.
    • Example 6 (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • Figure imgb0056
    • Step 1: (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(N-(methylsulfonyl)methylsulfonamido)-picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • A solution of methanesulfonyl chloride (21 mg, 184 µmol) in dichloromethane (0.5 mL) was added dropwise at 0°C to a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (example 1.07; 40 mg, 91.9 µmol) and triethylamine (27.9 mg, 276 µmol) in dichloromethane (1 mL). The ice bath was removed, then after 18 h the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) produced the title compound (42 mg, 77%). White foam, MS: 591.4 (M+H)+.
    • Step 2: (3aR,6aS)-3,5-Dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • To a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(N-(methylsulfonyl)methylsulfonamido)-picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (36 mg, 60.9 µmol) in tetrahydrofuran (0.5 mL) was added 1 M aq. sodium hydroxide solution (122 µl, 122 µmol), then after 1 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (29 mg, 93%). White foam, MS: 513.4 (M+H)+.
    • Example 7 (3aS,6aS)-5-(4-Sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester
  • Figure imgb0057
  • To a solution of (3-chloro-5-(methylsulfonyl)phenyl)methanol (intermediate 5; 23.3 mg, 105 µmol) in acetonitrile (4 ml) was added N,N'-carbonyldiimidazole (18.0 mg, 111 µmol) at room temperature, then after 2 h triethylamine (53.4 mg, 527 µmol) and 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride (intermediate 4; 35 mg, 105 µmol) were added and the reaction mixture was heated at reflux for 15 h. After cooling the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The aqueous layer was back-extracted with ethyl acetate, then the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in tert-butyl methyl ether to afford the title compound (26 mg, 46%). White solid, MS: 542.5 (M+H)+.
  • The following examples were prepared according to example 7, replacing 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride by the appropriate amine and (3-chloro-5-(methylsulfonyl)phenyl)methanol by the appropriate alcohol.
    Ex. Systematic Name Amine / Alcohol MS, m/e
    7.01 (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / (2-fluoro-4-(trifluoromethoxy)-phenyl)methanol 532.5 (M+H)+
    Figure imgb0058
    7.02 (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / (4-(trifluoromethoxy)-phenyl)methanol 514.6 (M+H)+
    Figure imgb0059
    7.03 (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4) / (4-(trifluoromethoxy)-phenyl)methanol 514.5 (M+H)+
    Figure imgb0060
    • Example 8 4-{(3aR,6aR)-5-[3-(4-Trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide
  • Figure imgb0061
  • To a white suspension of 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride (intermediate 4; 40 mg, 121 µmol), N-methylmorpholine (61.0 mg, 603 µmol) and 3-(4-(trifluoromethoxy)phenyl)propanoic acid (28.2 mg, 121 µmol) in N,N-dimethylformamide (5 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (45.8 mg, 121 µmol) at 0°C, and the ice bath was removed after 15 min. After 16 h, the reaction mixture was partitioned between dichloromethane and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. After trituration in tert-butyl methyl ether the precipitate was collected by filtration to afford the title compound (44 mg, 71%). White solid, MS: 512.5 (M+H)+.
  • The following examples were produced in analogy to example 8, replacing 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride by the appropriate amine and 3-(4-(trifluoromethoxy)phenyl)propanoic acid by the appropriate carboxylic acid.
    Ex. Systematic Name Amine / Carboxylic acid MS, m/e
    8.01 4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4) / (E)-3-(4-(trifluoromethoxy)-phenyl)acrylic acid 510.5 (M+H)+
    Figure imgb0062
    8.02 4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl] -benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 4-isopropoxy-2-naphthoic acid (CAS-RN 1368865-02-4) 508.4 (M+H)+
    Figure imgb0063
    8.03 4-{(3aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 1-(2,2,2-trifluoroethoxy)-isoquinoline- 3-carboxylic acid (CAS-RN 1096982-79-4) 549.6 (M+H)+
    Figure imgb0064
    8.04 4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 1-methyl-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (CAS-RN 1257122-42-1) 537.5 (M+H)+
    Figure imgb0065
    8.05 4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl] - benzene sulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 4-isopropoxyquinoline-2-carboxylic acid (CAS-RN 1406553-19-2) 509.6 (M+H)+
    Figure imgb0066
    8.06 4-[(3aS,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 4'-chlorobiphenyl-4-carboxylic acid (CAS-RN 5748-41-4) 510.5 (M+H)+
    Figure imgb0067
    8.07 4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxyphenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 3-(2-fluoro-4-(trifluoromethoxy)phenyl)-propanoic acid (CAS-RN 1240257-16-2) 530.3 (M+H)+
    Figure imgb0068
    8.08 4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1) / 3-(4-(trifluoromethoxy)-phenyl)propanoic acid 512.3 (M+H)+
    Figure imgb0069
    8.09 4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrr olo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide 4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4) / 3-(2-fluoro-4-(trifluoromethoxy)phenyl)-propanoic acid (CAS-RN 1240257-16-2) 530.5 (M+H)+
    Figure imgb0070
    • Examples 9A and 9B (-)-trans-3,5-Dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate and (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate
  • Figure imgb0071
     and
    Figure imgb0072
  • The racemate, trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (example 1.03; 60 mg, 117 µmol) was separated by preparative HPLC using a Reprosil Chiral-NR column as the stationary phase and heptane/ethanol 3:2 as the mobile phase. This produced the faster eluting (-)-enantiomer (example 9A; 23 mg, 38%; white solid, MS: 512.4 (M+H)+), and the slower eluting (+)-enantiomer (example 9B; 22 mg, 36%; orange foam, MS: 512.4 (M+H)+).
    • Intermediates Intermediate 1 (3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride Step 1: (3aR,6aS)-2-tert-Butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate
  • To a light brown solution of (3,5-dichlorophenyl)methanol (425 mg, 2.35 mmol) in dichloromethane (7 mL) was added N,N'-carbonyldiimidazole (401 mg, 2.47 mmol). The solution was stirred at room temperature for 3 h, then (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (CAS-RN 250275-15-1; 526 mg, 2.35 mmol) was added, then after 15 h the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (972 mg, 99%). Light brown viscous oil, MS: 359.2 (M-C(CH3)3+H)+.
    • Step 2: (3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride
  • To a solution of (3aR,6aS)-2-tert-butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate (962 mg, 2.32 mmol) in 2-propanol (4 mL) was added hydrochloric acid (5-6 M in 2-propanol) (11.6 mL, 57.9 mmol), then after 3 h the reaction mixture was evaporated. The residue taken up in ethyl acetate and a few drops of ethanol, then the precipitate was collected by filtration to produce the title compound (738 mg, 91%). White solid, MS: 315.3 (M+H)+.
  • The following intermediates were prepared according to intermediate 1, replacing (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by the appropriate amine and (3,5-dichlorophenyl)methanol by the appropriate alcohol.
    No. Systematic Name Amine Alcohol MS, m/e
    1.1 trans-3,5-dichlorobenzyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate hydrochloride trans-tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (CAS-RN 1251014-37-5) (3,5-dichlorophenyl)-methanol 329.4 (M+H)+
    1.2 (3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy -benzyl ester hydrochloride (3aR,6aR)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (intermediate 3.1) (4-(trifluoromethoxy)-phenyl)-methanol 331.5 (M+H)+
    • Intermediate 2 (E)-1-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)-phenyl)prop-2-en-1-one hydrochloride Step 1: (3aR,8aS)-tert-butyl 6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydro-pyrrolo[3,4-d]azepine-2(1H)-carboxylate
  • To a solution of (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate hydrochloride (CAS-RN 1251013-07-6; 1.5 g, 5.42 mmol), 4-methylmorpholine (2.19 g, 21.7 mmol) and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (1.26 g, 5.42 mmol) in N,N-dimethylformamide (30 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (2.06 g, 5.42 mmol) at 0°C. After 60 min the ice bath was removed, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with sat. aq. ammonium chloride solution, water, and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in heptane/ethyl acetate 9:1 to produce the title compound (2.20 g, 89%). White solid, MS: 399.5 (M - isobutene + H)+.
    • Step 2: (E)-1-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)-phenyl)prop-2-en-1-one hydrochloride
  • The title compound was produced in analogy to intermediate 1, step 2 from (3aR,8aS)-tert-butyl 6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate. White solid, MS: 355.5 (M+H)+.
  • The following intermediates were prepared according to intermediate 2, replacing (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate hydrochloride by the appropriate amine and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid by the appropriate carboxylic acid.
    No. Systematic Name Amine Carboxylic acid MS, m/e
    2.1 (4-ethoxyquinolin-2-yl)((3aS,6aS)-hexa-hydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (3aR,6aR)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (intermediate 3.1) 4-ethoxy-quinoline-2-carboxylic acid (CAS-RN 40609-78-7) 312.2 (M+H)+
    2.2 1-((3aS,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(4-(trifluoromethoxy)phenyl)propan-1-one dihydrochloride (3aR,6aR)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (intermediate 3.1) 3-(4-(trifluoromethoxy)-phenyl)-propanoic acid 329.5 (M+H)+
    • Intermediate 3 (3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Step 1: (3R,4R)-tert-Butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate
  • To a solution of (3R,4R)-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (CAS-RN 895245-32-6; 2.97 g, 12.8 mmol) and N,N-diisopropylethylamine (9.96 g, 77.0 mmol) in dichloromethane (70 ml) was added a solution of methanesulfonyl chloride (4.41 g, 38.5 mmol) in dichloromethane (5 ml) dropwise at 0°C, then after 1 h the reaction mixture was treated with sat. aq. ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. aq. sodium hydrogencarbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (4.22 g, 85%). Light yellow oil, MS: 332.4 (M - isobutene + H)+.
    • Step 2: (3aS,6aS)-tert-Butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • To a solution of (3R,4R)-tert-butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (4.22 g, 10.9 mmol) in acetonitrile (100 ml) was added potassium carbonate (15.1 g, 109 mmol) and phenylmethanamine (3.5 g, 32.7 mmol). The reaction mixture was heated at 95°C for 45 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with sat. aq. ammonium chloride solution, sat. aq. sodium hydrogencarbonate solution, and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; ethyl acetate - methanol gradient) produced the title compound (2.23 g 68%). Light yellow solid, MS: 303.5 (M+H)+.
    • Step 3: (3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • To a solution of (3aS,6aS)-tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.22 g, 7.34 mmol, Eq: 1.00) in methanol (20 mL) was added palladium (10% on carbon, 220 mg, 7.34 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (1 bar) at room temperature for 24 h, then insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated to produce the title compound (1.60 g, 100%). White waxy solid, MS: 213.5 (M+H)+.
    • Intermediate 3.1 (3aR,6aR)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • The title compound was produced in analogy to intermediate 3, replacing (3R,4R)-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate by (3S,4S)- tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (CAS-RN 895245-30-4). White waxy solid, MS: 213.3 (M+H)+.
    • Intermediate 4 4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride Step 1: (3aS,6aS)-tert-Butyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
  • To a solution of (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (intermediate 3; 206 mg, 970 µmol), N-methylmorpholine (294 mg, 2.91 mmol) and 4-sulfamoylbenzoic acid (203 mg, 970 µmol) in N,N-dimethylformamide (10 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (369 mg, 970 µmol) at 0°C, then after 10 min the ice-bath was removed. After 16 h the reaction mixture was partitioned between dichloromethane and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. After trituration in tert-butyl methyl ether the precipitate was collected by filtration to afford the title compound (348 mg, 91%). Light yellow solid, MS: 396.6 (M+H)+.
    • Step 2: 4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide hydrochloride (intermediate 4)
  • The title compound was produced in analogy to intermediate 1, step 2 from (3aS,6aS)-tert-butyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Light yellow solid, MS: 296.5 (M+H)+.
    • Intermediate 5 (3-Chloro-5-(methylsulfonyl)phenyl)methanol
  • To a solution of 3-chloro-5-(methylsulfonyl)benzoic acid (CAS-RN 151104-63-1; 500 mg, 2.13 mmol) in tetrahydrofuran (5 mL) was added slowly borane-tetrahydrofuran complex solution (1 M solution in tetrahydrofuran, 5.33 mL, 5.33 mmol) at 0°C, then after 3 h the ice-bath was removed and the rection mixture was stirred at room temperature overnight. The reaction mixture was then carefully treated with methanol (3 mL) and evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient afforded the title compound (428 mg, 91%). White solid, MS: 221.3 (M+H)+.
    • Intermediate 6 N-(5-Cyano-2-(hydroxymethyl)phenyl)pivalamide Step 1: Methyl 4-cyano-2-pivalamidobenzoate
  • To a solution of methyl 2-amino-4-cyanobenzoate (CAS-RN 159847-83-3; 776 mg, 4.4 mmol) in pyridine (6 mL) was added pivaloyl chloride (637 mg, 5.29 mmol) dropwise at 0°C, then after 2 h the reacion mixture was partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate/2-methyltetrahydrofuran. The organic layer was washed with water, 2 M aq. sodium carbonate solution, and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in ethyl acetate to afford the title compound (819 mg). The mother liquor was evaporated and triturated in tert-butyl methyl ether to produce a second crop of product (148 mg). Combined yield: 967 mg (84%). White solid, MS: 261.1 (M-H)-.
    • N-(5-cyano-2-(hydroxymethyl)phenyl)pivalamide
  • A suspension of calcium chloride (592 mg, 5.33 mmol) in ethanol (15 mL) was added at room temperature to a solution of methyl 4-cyano-2-pivalamidobenzoate (694 mg, 2.67 mmol) in tetrahydrofuran (15 mL), then sodium borohydride (403 mg, 10.7 mmol) was added. After 2 h the reaction mixture was poured upon ice water and sat. ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in tert-butyl methyl ether to produce the title compound (293 mg). The mother liquour was evaporated and purified by chromatography (dichloromethane-methanol gradient) to produce another crop of product (240 mg). Combined yield: 533 mg; (86%). White solid, MS: 231.1 (M-H)-.

Claims (16)

  1. Compounds of formula (I)
    Figure imgb0073
     wherein
    R1 is substituted C3-10-cycloalkyl, substituted C3-10-cycloalkyl-C1-12-alkyl, substituted phenyl, substituted phenyl-C1-12-alkyl, substituted phenoxy-C1-12-alkyl, substituted phenyl-C3-10-cycloalkyl, substituted phenyl-C2-7-alkenyl, substituted phenyl-C2-7-alkynyl, substituted naphthyl, substituted naphthyl-C1-12-alkyl, substituted naphthyloxy-C1-12-alkyl, substituted naphthyl-C2-7-alkenyl, substituted pyridinyl, substituted pyridinyl-C1-12-alkyl, substituted pyridinyl-C2-7-alkenyl, substituted pyridinyl-C2-7-alkynyl, substituted thiophenyl, substituted thiophenyl-C1-12-alkyl, substituted thiophenyl-C2-7-alkenyl, substituted thiophenyl-C2-7-alkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkyl-C1-12-alkyl, substituted phenyl, substituted phenyl-C1-12-alkyl, substituted phenoxy-C1-12-alkyl, substituted phenyl-C3-10-cycloalkyl, substituted phenyl-C2-7-alkenyl, substituted phenyl-C2-7-alkynyl, substituted naphthyl, substituted naphthyl-C1-12-alkyl, substituted naphthyloxy-C1-12-alkyl, substituted naphthyl-C2-7-alkenyl, substituted pyridinyl, substituted pyridinyl-C1-12-alkyl, substituted pyridinyl-C2-7-alkenyl, substituted pyridinyl-C2-7-alkynyl, substituted thiophenyl, substituted thiophenyl-C1-12-alkyl, substituted thiophenyl-C2-7-alkenyl, substituted thiophenyl-C2-7-alkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R7, R8 and R9;
    R2 is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted pyrrolyl and substituted thiophenyl are substituted with R10, R11 and R12;
    Y is -OC(O)-, -NR5C(O)-, -C(O)-, -S(O)2-,
    Figure imgb0074
    A is -N- or CH-;
    W is -O-, -S-, -NR6-, -C(O)-, -S(O)2-, or -CR3R4-;
    R3 and R4 are independently selected from H, halogen, C1-12-alkyl and C3-10-cycloalkyl;
    R5 and R6 are independently selected from H, C1-12-alkyl and C3-10-cycloalkyl;
    R7, R8 and R9 are independently selected from H, C1-12-alkyl, hydroxy-C1-12-alkyl, halo-C1-12-alkyl, hydroxyhalo-C1-12-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl-C1-12-alkyl, C3-10-cycloalkyl-C1-12-alkoxy, C3-10-cycloalkoxy, C3-10-cycloalkoxy-C1-12-alkyl, C3-10-cycloalkyl-C1-12-alkoxy-C1-12-alkyl, C1-12-alkoxy, C1-12-alkoxy-C1-12-alkyl, halo-C1-12-alkoxy, C1-12-alkoxyhalo-C1-12-alkyl, C1-12- alkoxy-C1-12-alkoxy, C1-12-alkoxy-C1-12-alkoxy-C1-12-alkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, C1-12-alkylsulfanyl, halo-C1-12-alkylsulfanyl, C3-10-cycloalkylsulfanyl, C1-12-alkylsulfinyl, halo-C1-12-alkylsulfinyl, C3-10-cycloalkylsulfinyl, C1-12-alkylsulfonyl, halo-C1-12-alkylsulfonyl, C3-10-cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted amino-C1-12-alkyl, wherein substituted aminosulfonyl, substituted amino and substituted amino-C1-12-alkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, C1-12-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl-C1-12-alkyl, hydroxy-C1-12-alkyl, C1-12-alkoxy-C1-12-alkyl, C1-12-alkylcarbonyl and C3-10-cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from C1-12-alkyl, halogen, halo-C1-12-alkyl, C1-12-alkoxy and halo-C1-12-alkoxy, wherein at least one of R7, R8 and R9 is not H;
    R10 is substituted aminosulfonyl, C1-12-alkoxycarbonyl, C1-12-alkylcarbonylamino, C1-12-alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino is substituted on the nitrogen atom with one to two substituents independently selected from H, C1-12-alkyl, C3-10-cycloalkyl, C3-10-cycloalkyl-C1-12-alkyl, hydroxy-C1-12-alkyl and C1-12-alkoxy-C1-12-alkyl;
    R11 and R12 are independently selected from H, C1-12-alkyl, C3-10-cycloalkyl, C1-12-alkoxy, halogen and halo-C1-12-alkyl;
    m, n, p and q are independently selected from 1 or 2;
    or pharmaceutically acceptable salts.
  2. A compound according to claim 1, wherein R1 is substituted phenyl, substituted phenyl-C1-12-alkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenyl-C1-12-alkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R7, R8 and R9.
  3. A compound according to any one of claims 1 to 2, wherein R2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R10, R11 and R12.
  4. A compound according to any one of claims 1 to 3, wherein Y is -OC(O)- or -C(O)-.
  5. A compound according to any one of claims 1 to 4, wherein A is -N-.
  6. A compound according to any one of claims 1 to 5, wherein W is -C(O)- or -S(O)2-.
  7. A compound according to any one of claims 1 to 6, wherein R10 is aminosulfonyl.
  8. A compound according to any one of claims 1 to 7, wherein R11 and R12 are independently selected from H, C1-12-alkyl and halogen.
  9. A compound according to any one of claims 1 to 8 of formula (la).
    Figure imgb0075
  10. A compound according to any one of claims 1 to 9, selected from
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;
    (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid;
    (3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5 -methanesulfonyl-benzyl ester;
    (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
    (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    4-{(3aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    4-[(3aS,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;
    4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;
    (+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    (-)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;
    and pharmaceutically acceptable salts thereof.
  11. A compound according to any one of claims 1 to 10, selected from
    (3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;
    (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;
    and pharmaceutically acceptable salts thereof.
  12. A compound according to any one of claims 1 to 11, wherein the compound is
    (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
    and pharmaceutically acceptable salts thereof.
  13. A process to prepare a compound according to any one of claims 1 to 12 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R1, R2, A, W, m, n, p and q are as defined above, Y is -OC(O)-.
    Figure imgb0076
  14. A compound according to any one of claims 1 to 12 for use as therapeutically active substance.
  15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a therapeutically inert carrier.
  16. A compound according to any one of claims 1 to 12 for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
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HRP20192274T1 (en) 2020-03-06
CR20150436A (en) 2015-09-16
KR20150126036A (en) 2015-11-10
SG11201507396YA (en) 2015-10-29
MY177574A (en) 2020-09-21
PH12015501934A1 (en) 2016-01-11
EA035015B1 (en) 2020-04-17
UA115354C2 (en) 2017-10-25
IL240796B (en) 2019-07-31
RS59682B1 (en) 2020-01-31
JP2016510780A (en) 2016-04-11
TWI678368B (en) 2019-12-01
EP2970256A1 (en) 2016-01-20
CN105073748B (en) 2018-06-01
MA38432B1 (en) 2017-09-29
WO2014139978A1 (en) 2014-09-18
BR112015022804A2 (en) 2017-07-18
US20180258095A1 (en) 2018-09-13
PH12015501934B1 (en) 2016-01-11
JP6483034B2 (en) 2019-03-13
AU2014230943B2 (en) 2016-12-01
CL2015002386A1 (en) 2016-03-04
AR095079A1 (en) 2015-09-16
AU2014230943B8 (en) 2016-12-15
US20150376194A1 (en) 2015-12-31
MX373247B (en) 2020-05-12
TW201522333A (en) 2015-06-16
CN105073748A (en) 2015-11-18
US10913745B2 (en) 2021-02-09
MX2015011311A (en) 2015-12-03
CA2901047A1 (en) 2014-09-18
DK2970256T3 (en) 2020-01-06
LT2970256T (en) 2020-01-10
SI2970256T1 (en) 2020-02-28
AU2014230943A1 (en) 2015-08-27
ES2763417T3 (en) 2020-05-28
HK1211935A1 (en) 2016-06-03
EA201591497A1 (en) 2015-12-30

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